Anti-tnf-alpha antibodies and their uses
AssigneeAbbVie Biotherapeutics Inc.
InventorsFiona A. Harding, Yoshiko Akamatsu, Robert B. Dubridge, David B. Powers
Life of this patent
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Abstract
The present disclosure relates to antibodies directed to the tumor necrosis factor alpha (“TNF-α”) and uses of such antibodies, for example, to treat diseases associated with the activity and/or overproduction of TNF-α.
Claims80
An anti-TNF-α antibody or an anti-TNF-α binding fragment of an antibody which comprises six complementarity determining regions (“CDRs”) having amino acid sequences corresponding to SEQ ID NO:5 (CDR-H1), SEQ ID NO:6 (CDR-H2), SEQ ID NO:7 (CDR-H3), SEQ ID NO:8 (CDR-L1), SEQ ID NO:9 (CDR-L2) and SEQ ID NO:10 (CDR-H3), said CDR sequences being the CDR sequences of antibody D2E7, wherein said CDRs include at least one substitution selected from S3K in CDR-L2, S3R in CDR-L2, T4H in CDR-L2, T4Q in CDR-L2, T4F in CDR-L2, T4W in CDR-L2, T4Y in CDR-L2, L5R in CDR-L2, L5K in CDR-L2, Q6R in CDR-L2, Y2H in CDR-H1, A3G in CDR-H1, and T3N in CDR-H2, and optionally one or more additional mutations or combinations of mutations selected from one or more of Tables 11 and 13 to 25, wherein the six CDRs altogether have up to 17 amino acid substitutions as compared to CDR sequences of the antibody D2E7.
An anti-TNF-α antibody or an anti-TNF-α binding fragment of an antibody which comprises six CDRs having amino acid sequences corresponding to SEQ ID NO:5 (CDR-H1), SEQ ID NO:6 (CDR-H2), SEQ ID NO:7 (CDR-H3), SEQ ID NO:8 (CDR-L1), SEQ ID NO:9 (CDR-L2) and SEQ ID NO:10 (CDR-H3), said CDR sequences being the CDR sequences of antibody D2E7, wherein said CDRs include at least one substitution selected from T4F in CDR-L2, T4W in CDR-L2, T4Y in CDR-L2, L5R in CDR-L2, L5K in CDR-L2, Q6R in CDR-L2, Y2H in CDR-H1, A3G in CDR-H1, and T3N in CDR-H2 and optionally one or more additional mutations or combinations of mutations selected from one or more of Tables 11 and 13 to 25, wherein the six CDRs altogether have up to 17 amino acid substitutions as compared to CDR sequences of the antibody D2E7.
An anti-TNF-α antibody or an anti-TNF-α binding fragment of an antibody which comprises six CDRs having amino acid sequences corresponding to SEQ ID NO:5 (CDR-H1), SEQ ID NO:6 (CDR-H2), SEQ ID NO:7 (CDR-H3), SEQ ID NO:8 (CDR-L1), SEQ ID NO:9 (CDR-L2) and SEQ ID NO:10 (CDR-H3), said CDR sequences being the CDR sequences of antibody D2E7, wherein said CDRs include at least one substitution selected from T4F in CDR-L2, T4W in CDR-L2, T4Y in CDR-L2, L5R in CDR-L2, L5K in CDR-L2, Q6R in CDR-L2, Y2H in CDR-H1, A3G in CDR-H1, and T3N in CDR-H2, and optionally one or more additional mutations or combinations of mutations selected from one or more of Tables 11 and 13 to 18, wherein the six CDRs altogether have up to 17 amino acid substitutions as compared to CDR sequences of the antibody D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim wherein the six CDRs altogether have up to 16, up to 15, up to 14, up to 13, up to 12, up to 11, up to 10, up to 9, up to 8, up to 7, or up to 6 amino acid substitutions as compared to CDR sequences of the antibody D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim, wherein any individual CDR has no more than three amino acid substitutions as compared to the corresponding CDR sequence of the antibody D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim, wherein any individual CDR has no more than two amino acid substitutions as compared to the corresponding CDR sequence of the antibody D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution S3K in CDR-L2 as compared to CDR-L2 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution S3R in CDR-L2 as compared to CDR-L2 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution T4H in CDR-L2 as compared to CDR-L2 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution T4Q in CDR-L2 as compared to CDR-L2 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution T4F in CDR-L2 as compared to CDR-L2 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution T4W in CDR-L2 as compared to CDR-L2 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution T4Y in CDR-L2 as compared to CDR-L2 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution L5R in CDR-L2 as compared to CDR-L2 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution L5K in CDR-L2 as compared to CDR-L2 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution Q6R in CDR-L2 as compared to CDR-L2 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution D1G in CDR-H1 as compared to CDR-H1 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution Y2H in CDR-H1 as compared to CDR-H1 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution A3G in CDR-H1 as compared to CDR-H1 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has the substitution T3N in CDR-H2 as compared to CDR-H2 of D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which is a monoclonal antibody or anti-TNF-α binding fragment of a monoclonal antibody, respectively.
The anti-TNF-α antibody or an anti-TNF-α binding fragment of any preceding claim which is a human or humanized antibody, or anti-TNF-α binding fragment of a humanized or humanized antibody, respectively.
The anti-TNF-α antibody or an anti-TNF-α binding fragment of any preceding claim which is an IgG.
The anti-TNF-α antibody or an anti-TNF-α binding fragment of any preceding claim which includes one or more mutations in the Fc region that increase ADCC activity.
The anti-TNF-α antibody or an anti-TNF-α binding fragment of any preceding claim which is non-fucosylated.
The anti-TNF-α antibody or an anti-TNF-α binding fragment of any preceding claim which includes one or more mutations in the Fc region that increase binding to FcγR.
The anti-TNF-α antibody or an anti-TNF-α binding fragment of any preceding claim which includes one or mutations in the Fc region that decrease ADCC activity.
The anti-TNF-α antibody or an anti-TNF-α binding fragment of any preceding claim which has, other than said one or more mutations, a VH sequence corresponding to SEQ ID NO:2 and a VL sequence corresponding to SEQ ID NO:4.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which has an affinity that is 1.1 to 4 fold greater than the affinity of an antibody having a VH sequence corresponding to SEQ ID NO:2 and a VL sequence corresponding to SEQ ID NO:4.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which is purified.
An anti-TNF-α antibody or an anti-TNF-α binding fragment of an antibody which comprises six CDRs having amino acid sequences corresponding to SEQ ID NO:5 (CDR-H1), SEQ ID NO:6 (CDR-H2), SEQ ID NO:7 (CDR-H3), SEQ ID NO:8 (CDR-L1), SEQ ID NO:9 (CDR-L2) and SEQ ID NO:10 (CDR-H3), said CDR sequences being the CDR sequences of antibody D2E7, wherein said CDRs include a substitution or combination of substitutions selected from R7Q;
- A11S;
- R7Q+A11S;
- N8T;
- N8T+A11S;
- 16T;
- A11G;
- 16T+A11G;
- Q4G;
- Q4G+A11S;
- Q4G+A11G;
- Q4H;
- Q4H+A11S;
- Q4R;
- Q4R+A11S;
- G5S+A11S;
- N8S+A11S;
- 16T+A11S;
- N8T+A11G in CDR-L1, and optionally one or more additional mutations or combinations of mutations selected from one or more of Tables 12 to 25, wherein the six CDRs altogether have up to 17 amino acid substitutions as compared to CDR sequences of the antibody D2E7.
An anti-TNF-α antibody or an anti-TNF-α binding fragment of an antibody which comprises six CDRs having amino acid sequences corresponding to SEQ ID NO:5 (CDR-H1), SEQ ID NO:6 (CDR-H2), SEQ ID NO:7 (CDR-H3), SEQ ID NO:8 (CDR-L1), SEQ ID NO:9 (CDR-L2) and SEQ ID NO:10 (CDR-H3), said CDR sequences being the CDR sequences of antibody D2E7, wherein said CDRs includes a substitution or combination of substitutions selected from R7Q;
- A11S;
- R7Q+A11S;
- N8T;
- N8T+A11S;
- 16T;
- A11G;
- 16T+A11G;
- Q4G;
- Q4G+A11S;
- Q4G+A11G;
- Q4H;
- Q4H+A11S;
- Q4R;
- Q4R+A11S;
- G5S+A11S;
- N8S+A11S;
- 16T+A11S;
- N8T+A11G in CDR-L1, and optionally one or more additional mutations or combinations of mutations selected from one or more of Tables 12 to 18, wherein the six CDRs altogether have up to 17 amino acid substitutions as compared to CDR sequences of the antibody D2E7.
An anti-TNF-α antibody or an anti-TNF-α binding fragment of an antibody which comprises six CDRs having amino acid sequences corresponding to SEQ ID NO:5 (CDR-H1), SEQ ID NO:6 (CDR-H2), SEQ ID NO:7 (CDR-H3), SEQ ID NO:8 (CDR-L1), SEQ ID NO:9 (CDR-L2) and SEQ ID NO:10 (CDR-H3), said CDR sequences being the CDR sequences of antibody D2E7, wherein said CDRs include the substitutions G5S+A11S in CDR-L1, and optionally one or more additional mutations or combinations of mutations selected from one or more of Tables 11 to 25, wherein the six CDRs altogether have up to 17 amino acid substitutions as compared to CDR sequences of the antibody D2E7.
An anti-TNF-α antibody or an anti-TNF-α binding fragment of an antibody which comprises six CDRs having amino acid sequences corresponding to SEQ ID NO:5 (CDR-H1), SEQ ID NO:6 (CDR-H2), SEQ ID NO:7 (CDR-H3), SEQ ID NO:8 (CDR-L1), SEQ ID NO:9 (CDR-L2) and SEQ ID NO:10 (CDR-H3), said CDR sequences being the CDR sequences of antibody D2E7, wherein said CDRs include the substitutions G5S+A11G in CDR-L1, and optionally one or more additional mutations or combinations of mutations selected from one or more of Tables 11 to 25, wherein the six CDRs altogether have up to 17 amino acid substitutions as compared to CDR sequences of the antibody D2E7.
An anti-TNF-α antibody or an anti-TNF-α binding fragment of an antibody which comprises six CDRs having amino acid sequences corresponding to SEQ ID NO:5 (CDR-H1), SEQ ID NO:6 (CDR-H2), SEQ ID NO:7 (CDR-H3), SEQ ID NO:8 (CDR-L1), SEQ ID NO:9 (CDR-L2) and SEQ ID NO:10 (CDR-H3), said CDR sequences being the CDR sequences of antibody D2E7, wherein said CDRs include at least one substitution selected from S3N in CDR-L2, T4V in CDR-L2, Q6K in CDR-L2, and D1G in CDR-H1 and at least one substitution or combination of substitutions selected from Tables 11, 12 and 25, and optionally one or more additional mutations or combinations of mutations selected from one or more of Tables 11 to 25, wherein the six CDRs altogether have up to 17 amino acid substitutions as compared to CDR sequences of the antibody D2E7.
An anti-TNF-α antibody or an anti-TNF-α binding fragment of an antibody which comprises six complementarity determining regions (“CDRs”) having amino acid sequences corresponding to SEQ ID NO:5 (CDR-H1), SEQ ID NO:6 (CDR-H2), SEQ ID NO:7 (CDR-H3), SEQ ID NO:8 (CDR-L1), SEQ ID NO:9 (CDR-L2) and SEQ ID NO:10 (CDR-H3), said CDR sequences being the CDR sequences of antibody D2E7, wherein said CDR-L2 CDR includes at least one combination of substitutions selected from:
- a. S3K, T4H, L5R and Q6R;
- b. S3K, T4Q, L5R and Q6K;
- c. S3K, T4Y and L5K;
- d. S3K and T4Y;
- e. S3N, T4V, L5R and Q6K;
- f. S3N, T4W, L5R and Q6R;
- g. S3R, T4F and L5R;
- h. S3R, T4F, L5R and Q6R;
- i. S3R, T4H and Q6K;
- j. S3R, T4W, L5K and Q6R;
- k. T4H, L5K and Q6K;
- l. T4H, L5K and Q6R;
- m. T4W, L5R and Q6R;
- and
- n. T4Y and L5R,
- optionally wherein said anti-TNF-α antibody or anti-TNF-α binding fragment comprises one or more additional mutations or combinations of mutations selected from one or more of Tables 11 to 24, wherein the six CDRs altogether have up to 17 amino acid substitutions as compared to CDR sequences of the antibody D2E7.
The anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim which is a bispecific antibody or a TNF-α binding fragment of a bispecific antibody.
A pharmaceutical composition comprising an anti-TNF-α antibody or anti-TNF-α binding fragment according to any preceding claim and a pharmaceutically acceptable carrier.
A nucleic acid comprising a nucleotide sequence encoding an anti-TNF-α antibody or anti-TNF-α binding fragment of any preceding claim.
Dependencies are inferred from the claim text.